ORCID Profile
0000-0002-4630-7484
Current Organisations
Ludwig-Maximilians-Universität München
,
UCL Queen Square Institute of Neurology
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Publisher: Wiley
Date: 11-2011
DOI: 10.1002/ANA.22535
Publisher: Springer Science and Business Media LLC
Date: 09-08-2016
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.NBD.2014.02.001
Abstract: Gephyrin is a postsynaptic scaffolding protein, essential for the clustering of glycine and γ-aminobutyric acid type-A receptors (GABAARs) at inhibitory synapses. An impairment of GABAergic synaptic inhibition represents a key pathway of epileptogenesis. Recently, exonic microdeletions in the gephyrin (GPHN) gene have been associated with neurodevelopmental disorders including autism spectrum disorder, schizophrenia and epileptic seizures. Here we report the identification of novel exonic GPHN microdeletions in two patients with idiopathic generalized epilepsy (IGE), representing the most common group of genetically determined epilepsies. The identified GPHN microdeletions involve exons 5-9 (Δ5-9) and 2-3 (Δ2-3), both affecting the gephyrin G-domain. Molecular characterization of the GPHN Δ5-9 variant demonstrated that it perturbs the clustering of regular gephyrin at inhibitory synapses in cultured mouse hippoc al neurons in a dominant-negative manner, resulting in a significant loss of γ2-subunit containing GABAARs. GPHN Δ2-3 causes a frameshift resulting in a premature stop codon (p.V22Gfs*7) leading to haplo-insufficiency of the gene. Our results demonstrate that structural exonic microdeletions affecting the GPHN gene constitute a rare genetic risk factor for IGE and other neuropsychiatric disorders by an impairment of the GABAergic inhibitory synaptic transmission.
Publisher: Cold Spring Harbor Laboratory
Date: 23-02-2021
DOI: 10.1101/2021.02.19.21251501
Abstract: Cognitive impairment is a common comorbidity of epilepsy, and adversely impacts people with both frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). While the underlying neural substrates in TLE have been extensively investigated, functional imaging studies in FLE are scarce. In this study, we profiled cognitive dysfunction in FLE, and directly compared FLE and TLE patients to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE, and 52 controls), using neuropsychological tests and four functional MRI tasks probing the neural correlates of expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-epileptic drug load. We devised a multiscale approach to map the landscape of brain activation and deactivation during cognition, and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects (i) across intrinsic functional systems, and (ii) along the principal functional connectivity gradient, which encodes a continuous transition from lower-level sensory to higher-order transmodal brain areas. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, and reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. Functional abnormalities in FLE were modulated by disease load. Patterns of dysfunction in FLE were broadly similar to those in TLE, but some traits were syndrome-specific: altered default-mode deactivation was more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands was more marked in TLE. Our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies, and sheds light on system behavior that may be amenable to future remediation strategies.
Publisher: Frontiers Media SA
Date: 09-05-2019
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Christian Vollmar.